Innovative strategies are needed to improve the prognosis of patients with adenocarcinomas arising in the gastrointestinal tract. We are studying the interaction of modulatory & cytotoxic agents with fluorouracil in vitro to define optimal sequences for potential clinical use. Studies are designed to elucidate the optimal schedule of administration & mechanism of action of novel agents with activity against colon cancer cell lines to facilitate their rational clinical use. We implement clinical trials that incorporate clinical pharmacokinetic, biochemical &/or molecular endpoints. New analytic assay methods are developed to measure the pharmacokinetics & intracellular pharmacodynamics of the anticancer agents. Our goal is to develop new agents & drug combinations for patients with GI cancers, & to develop strategies that selectively target cancer cells with genomic instability &/or impaired programmed cell death pathways.